CLUSTERING OF MISSENSE MUTATIONS IN THE ATAXIA-TELANGIECTASIA GENE INA SPORADIC T-CELL LEUKEMIA

Ataxia-telangiectasia (A-T) is a recessive multi-system disorder cause d by mutations in the ATM gene(1,2) at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients(4) and has long been associated with chromosomal instabil ity(5), By analysing tumour DMA from patients with sporadic T-cell pro lymphocytic leukaemia (T-PLL), a rare clonal malignancy with similarit ies to a mature T-cell leukaemia seen in A-T-6,T-7, We demonstrate a h igh frequency of ATM mutations in T-PLL. In marked contrast to the ATM mutation pattern in A-T, the most frequent nucleotide changes in this leukaemia were missense mutations. These clustered in the region corr esponding to the kinase domain, which is highly conserved in ATM-relat ed proteins in mouse, yeast and Drosophila. The resulting amino-acid s ubstitutions are predicted to interfere with ATP binding or substrate recognition. Two of seventeen mutated T-PLL samples had a previously r eported A-T allele. In contrast, no mutations were detected in the p53 gene, suggesting that this tumour suppressor is not frequently altere d in this leukaemia. Occasional missense mutations in ATM were also fo und in tumour DNA from patients with B-cell non-Hodgkin's lymphomas (B -NHL) and a B-NHL cell line. The evidence of a significant proportion of loss-of-function mutations and a complete absence of the normal cop y of ATM in the majority of mutated tumours establishes somatic inacti vation of this gene in the pathogenesis of sporadic T-PLL and suggests that ATM acts as a tumour suppressor. As constitutional DNA was not a vailable, a putative hereditary predisposition to T-PLL will require f urther investigation.